Physical Fitness Training in Patients with Subacute Stroke ...

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BMJ: first published as 10.1136/bmj.l5101 on 18 September 2019. Downloaded from on 12 January 2024 by guest. Protected by copyright.

Physical Fitness Training in Patients with Subacute Stroke

(PHYS-STROKE): multicentre, randomised controlled, endpoint

blinded trial

Alexander H Nave,1,2,3,4 Torsten Rackoll,1,5 Ulrike Grittner,4,6 Holger Bl?sing,7 Anna Gorsler,5 Darius G Nabavi,8 Heinrich J Audebert,1,2 Fabian Klostermann,2 Ursula M?ller-Werdan,9 Elisabeth Steinhagen-Thiessen,9 Andreas Meisel,1,2,10 Matthias Endres,1,2,3,4,10,11 Stefan Hesse,12 Martin Ebinger,1,12 Agnes Fl?el1,13,14

For numbered affiliations see end of the article.

Correspondence to: A Fl?el agnes.floeel@med.unigreifswald.de (ORCID 0000-0002-1475-5872)

Additional material is published online only. To view please visit the journal online.

Cite this as: BMJ 2019;366:l5101

Accepted: 23 July 2019

ABSTRACT OBJECTIVE To determine the safety and efficacy of aerobic exercise on activities of daily living in the subacute phase after stroke.

DESIGN Multicentre, randomised controlled, endpoint blinded trial.

SETTING Seven inpatient rehabilitation sites in Germany (2013-17).

PARTICIPANTS 200 adults with subacute stroke (days 5-45 after stroke) with a median National Institutes of Health stroke scale (NIHSS, range 0-42 points, higher values indicating more severe strokes) score of 8 (interquartile range 5-12) were randomly assigned (1:1) to aerobic physical fitness training (n=105) or relaxation sessions (n=95, control group) in addition to standard care.

INTERVENTION Participants received either aerobic, bodyweight supported, treadmill based physical fitness training or relaxation sessions, each for 25 minutes, five times weekly for four weeks, in addition to standard rehabilitation therapy. Investigators and endpoint assessors were masked to treatment assignment.

MAIN OUTCOME MEASURES The primary outcomes were change in maximal walking speed (m/s) in the 10 m walking test and

WHAT IS ALREADY KNOWN ON THIS TOPIC

Current guidelines endorse cardiorespiratory training within post-stroke rehabilitation programmes Large randomised controlled trials of this recommendation are scarce, resulting in inconclusive data on efficacy for disability (activities of daily living) and safety of physical fitness training after stroke

WHAT THIS STUDY ADDS

Results suggest that in adults with moderate to severe subacute stroke, in addition to standard rehabilitation care, aerobic, bodyweight supported, treadmill based fitness training did not improve maximal walking speed or activities of daily living compared with relaxation The rate of serious adverse events was higher in the aerobic physical fitness training group than relaxation group Compared with current guideline recommendations, these results do not appear to support the use of aerobic, bodyweight supported, treadmill based fitness training in this stroke population

change in Barthel index scores (range 0-100 points, higher scores indicating less disability) three months after stroke compared with baseline. Safety outcomes were recurrent cardiovascular events, including stroke, hospital readmissions, and death within three months after stroke. Efficacy was tested with analysis of covariance for each primary outcome in the full analysis set. Multiple imputation was used to account for missing values.

RESULTS Compared with relaxation, aerobic physical fitness training did not result in a significantly higher mean change in maximal walking speed (adjusted treatment effect 0.1 m/s (95% confidence interval 0.0 to 0.2 m/s), P=0.23) or mean change in Barthel index score (0 (-5 to 5), P=0.99) at three months after stroke. A higher rate of serious adverse events was observed in the aerobic group compared with relaxation group (incidence rate ratio 1.81, 95% confidence interval 0.97 to 3.36).

CONCLUSIONS Among moderately to severely affected adults with subacute stroke, aerobic bodyweight supported, treadmill based physical fitness training was not superior to relaxation sessions for maximal walking speed and Barthel index score but did suggest higher rates of adverse events. These results do not appear to support the use of aerobic bodyweight supported fitness training in people with subacute stroke to improve activities of daily living or maximal walking speed and should be considered in future guidelines.

TRIAL REGISTRATION NCT01953549.

Introduction Despite encouraging advances in the early treatment of stroke,1 at least one third of the 10 million people worldwide with new stroke each year2 remain functionally dependent and as a result experience impairments in activities of daily living.3 4 The number of stroke survivors with impairments in activities of daily living is increasing, leading to more people with stroke who are dependent on rehabilitation interventions.5 To date, no drug treatments are available to enhance rehabilitation. Treadmill based physical fitness training constitutes a non-drug approach in stroke rehabilitation that might not only prevent deconditioning but also show associated

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BMJ: first published as 10.1136/bmj.l5101 on 18 September 2019. Downloaded from on 12 January 2024 by guest. Protected by copyright.

benefits on activities of daily living, such as walking and climbing stairs.6-8

A meta-analysis of small randomised controlled trials showed improvements in speed and tolerance of walking after physical fitness training in stroke survivors.6 The studies have, however, varied in type and intensity of exercise, timing of initiation after stroke, and control groups.7 9-11 The American Heart Association/American Stroke Association currently recommends aerobic exercise for stroke survivors, with three to five sessions weekly lasting 20 to 60 minutes and at a heart rate of 55-80% of the maximum. Applied in the subacute stage after stroke, aerobic exercise is thought to promote neuroplasticity and to have beneficial effects on functional outcomes.7 So far, nine randomised controlled trials (n=324) have compared the effects of aerobic physical fitness training on maximal walking speed--an important indicator of mobility in everyday life6--with a control intervention. However, only two of these studies (n=73) enrolled participants within the first six weeks after stroke, and these participants showed improvement in maximal walking speed post-intervention.6 For activities of daily living and disability, two small randomised rehabilitation trials (n=199) that applied 400-540 minutes of physical fitness training in the early and late subacute stage after stroke found an increase in the Barthel index score, a disability scale widely used in the clinical setting to measure activities of daily living.12 13 Meta-analyses have, however, indicated that the evidence for improvement in Barthel index scores after physical fitness training is still inconclusive.6

Visual Abstract

PHYS-STROKE trial

Physical fitness training in patients with subacute stroke

Summary

Physical fitness training was not superior to a relaxation intervention in terms of maximal walking speed and activities of daily living. A higher rate of serious adverse events was observed

Population

200

Adults with subacute stroke and moderate to severe impairment in activities of daily living

Sex:

Mean age:

% women

Study design

Randomised controlled trial

Endpoint blinded

Participants recruited at sites

Comparison Physical fitness training

Relaxation

Aerobic, bodyweight supported, treadmill based for mins ( sessions)

Progressive muscle relaxation for mins

( sessions)

105

95

Outcomes

Adjusted treatment effect* Mean % CI; P value

Change in maximal walking speed after months (m/s)

0.4

0.1 0.0 to 0.2; P=0.23

0.3

A change of . m/s would be clinically significant

Previously, the larger Locomotor Experience Applied Post-Stroke (LEAPS) trial randomised 408 participants to treadmill based locomotor training either two or six months after stroke, or to a progressive exercise programme at home, and did not detect a difference in treatment effects.11 LEAPS did not, however, apply an aerobic physical fitness training early after stroke.

We performed a multicentre, randomised controlled trial in adults with stroke in the early subacute phase (days 5-45 after stroke) to determine the efficacy of aerobic treadmill based, physical fitness training on maximal walking speed and activities of daily living compared with relaxation as a control intervention.

Methods Study design The study protocol for the multicentre, randomised controlled, endpoint blinded Physical Fitness Training in Patients with Subacute Stroke (PHYS-STROKE) trial is available online () and has been published previously.14 All participants provided informed consent. Adults were enrolled at seven inpatient rehabilitation sites in Berlin, Germany, and the surrounding area. A medical monitoring and independent data safety and monitoring board was appointed by the Centre for Stroke Research Berlin. Guidance of study centre representatives was maintained by regular telephone contact and study visits by members of the coordinating trial centre at the Centre for Stroke Research Berlin. To determine eligibility for the trial, trained trial physicians screened people with an imaging confirmed diagnosis of ischaemic or haemorrhagic stroke who had been admitted to hospital within a recruiting centre.

Participants People were eligible for the trial if they were aged at least 18 years, were in the subacute phase of ischaemic or haemorrhagic stroke (days 5-45 after stroke onset), were able to sit unsupported for at least 30 seconds, were considered able to perform aerobic exercise by the responsible trial physician, and had a Barthel index score of 65 or less at the time of enrolment. The Barthel index measures activities of daily living based on 10 items, with scores ranging from 0 to 100 points-- higher scores indicating less dependence.15 Key exclusion criteria were intracranial haemorrhage from a ruptured aneurysm or arteriovenous malformation, inability to perform required physical exercise, assisted walking before stroke, or severe cardiac or psychiatric comorbidities. If study requirements were met, trial physicians assessed information on stroke type and medical conditions after written informed consent was obtained. The supplementary file lists the inclusion and exclusion criteria.

Change in barthel index after months (score)

30

0 -5 to 5; P=0.99

30

A change of points would be clinically significant

*Adjusted for baseline value, sex, functional ambulation category, and centre

: NCT ? BMJ Publishing group Ltd.

Randomisation and blinding Participants were stratified by age (65 years, >65 years), functional ambulation category (scores 3, >3), and centre and were randomised using a web based tool in a 1:1 ratio to receive aerobic physical

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BMJ: first published as 10.1136/bmj.l5101 on 18 September 2019. Downloaded from on 12 January 2024 by guest. Protected by copyright.

fitness training or relaxation sessions (control group) in addition to standard care.16 The functional ambulation category is a six point scale that assesses dependency on walking aids, with higher scores indicating less dependency. Trained study assessors (physiotherapists, occupational therapists) collected information on participant characteristics and clinical data from chart reviews at baseline visits and carried out outcome assessments at baseline and follow-up. Study assessors and the trial statistician were blinded to the intervention allocation.

Interventions Therapists at each rehabilitation site performed interventions according to standardised protocols taught by a manual and two day training course. The study interventions were applied during inpatient stay at the rehabilitation centre, in addition to standard rehabilitation therapy according to German guide lines (bar-frankfurt.de). The supplementary file provides detailed information on the amount and content of standard care. Each study session was for 50 minutes (therapist led), comprising 25 minutes of core intervention (training aimed at target heart rate or relaxation time), and took place five times weekly over four weeks (20 sessions in total). The start and end of each intervention session as well as the duration of the core intervention were documented for each participant. An intervention period of four weeks was chosen to ensure intervention sessions were applied during the length of the inpatient stay at the rehabilitation centres. This also enabled the assessment of short term outcomes at three months after stroke.

The supplementary appendix provides a detailed description of the aerobic physical fitness training and relaxation interventions. Briefly, the aerobic physical fitness training sessions included treadmill based, bodyweight supported training at a cardiorespiratory active (aerobic) level to reach a target heart rate for 25 minutes. The target heart rate was calculated by the formula 180 minus years of age, a pragmatic decision, which resembles conventional approaches for calculation of target heart rate that is 50-60% of each participant's maximum heart rate (see supplementary appendix). If participants used blockers, we reduced the target heart rate by 10 beats per minute. Participants used a bodyweight supported treadmill (Multi-disk treadmill Callis, Model Therapie; Sprintex Trainingsger?te, Kleines Wiesental, Germany; RehaStim, Berlin, Germany) if their functional ambulation category score was 3-5 or an electromechanical gait trainer (Gait Trainer GT1; Reha-Stim, Berlin, Germany) if their score was 0-2. The amount of bodyweight support was applied as required. If necessary, one or two therapists assisted with leg movement, such as extending hip and knee, shifting body weight, or setting the paretic leg in the case of severe paresis of the peroneus muscles. Participants used the same orthoses during the intervention as during standard care physiotherapy. Each training session, including preparation time and a warm-up and cool-down

phase, lasted 50 minutes and comprised 25 minutes of active training at aimed target heart rate, depending on each participant's ability, as recommended in current guidelines.7 To ensure target heart rate was maintained, heart rate during training was controlled through a pulse sensor (Polar FT1 HRM, Polar Electro Oy, Kempele, Finland) and a screen attached to the treadmill or gait trainer. Reduction of bodyweight support and an increase of belt speed or increase of inclination, or both was used to reach the target heart rate throughout the four week intervention, and thus to constantly induce aerobic training effects. The trainers documented changes of these variables during the intervention period and individual perceived exertion after each training session in intervention diaries. To prevent falls, participants were equipped with a modified parachute harness (Belt system; Reha-Stim, Berlin, Germany).

Relaxation sessions were performed as an active control and focused on contraction and relaxation of muscle groups in the face, arms, shoulders, back, and abdomen for 25 minutes. Participants were instructed to contract the muscles for five to 10 seconds then to relax for 30-40 seconds and were encouraged to pay attention to the feelings of warmth and heaviness. Sessions aimed to promote mental and physical relaxation and avoid any cardiovascular stress. Participants' heart rates were monitored during the relaxation sessions, and ratings of perceived exertion were assessed at the end of each session. Participants in both groups received individual attention during each session to achieve comparability.

No specific treatment policy was prescribed after the intervention period. If participants stopped the intervention prematurely, we continued clinical follow-up at set time points. Participants were analysed in the per protocol analysis if they received 75% or more of the scheduled intervention sessions, had not suspended the intervention for more than five consecutive days, and had participated in the followup visit three months after stroke.

Outcome measures Study visits for outcome assessment were performed before and after the intervention period as well as three and six months after stroke. The primary outcome measures were change in maximal walking speed (assessed in m/s) and change in Barthel index scores three months after stroke compared with baseline in the intention-to-treat analysis. Maximal walking speed was assessed in a 10 m walk test.17 Participants were asked to walk at maximal speed for 14 m--2 m for acceleration and 2 m for deceleration, with markings on the floor for starting point, at 2 m (start of measurement) and 12 m (end of measurement). The time taken for the walk was measured manually using an electronic time watch for all participants and was additionally controlled with a light beam to trigger an additional watch (Wilhelm K?ster Ingenieur f?r Zeitmessung, Ditzingen, Germany). The test was performed twice and mean speed calculated to avoid

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test-retest error. Prespecified secondary outcomes included the six minute walk test (in metres), Rivermead mobility index18 (range 0-15, with higher scores indicating better mobility), actigraphy for 24 hours (in steps daily, assessed with GT3x; Actigraph, Pensacola, FL), modified Rankin scale (mRS) score (a scale assessing disability after stroke; ranging from 0 for no symptoms to 6 for death), as well as measures of cognition, motor function, spasticity, mood, and sleep at follow-up compared with baseline. Additionally, in a per protocol dataset we analysed changes in maximal walking speed and Barthel index score three months after stroke compared with baseline. Prespecified biomarker and imaging outcome measures will be analysed separately within an accompanying study,19 as described in the statistical analysis plan. The supplementary appendix describes the assessments of secondary outcomes. Main prespecified subgroup analyses included dichotomisation of impairment scores (National Institutes of Health stroke scale (NIHSS)20 assessed on days 3-5 after stroke, a scale that measures neurological deficits, ranging from 0 to 42 points, with higher values indicating more severe strokes, and functional ambulation category), type of stroke, time of study inclusion, and age and sex of participants. We carried out additional post hoc exploratory analyses of differential treatment effects for continuous variables using splines.21

Primary safety outcomes included the serious adverse events of recurrent cardiovascular events, including stroke, admission to an acute care hospital, or death within three months after stroke. Trial physicians reported these outcomes to the coordinating trial centre within 24 hours. The adverse events of self reported pain, fatigue, dizziness, and number and nature of falls during the intervention period were recorded after each intervention session. We reported adverse events to the data safety monitoring board on a regular basis.

Statistical analysis To show the superiority of the aerobic physical fitness training over relaxation intervention, the study was powered on the primary outcome measures to detect a clinically meaningful difference of 0.13 m/s in maxi mal walking speed (common standard deviation of 0.25 m/s) or 10 points in Barthel index score (common standard deviation of 21 points).14 Assumptions were based on reported clinical differences from a previous study of another working group (n=155).13 Overall, 172 participants (86 in each group) were needed to provide 80% power to detect a statistically significant treatment effect for each of the primary endpoints (maximal walking speed and Barthel index score at three months compared with baseline; two sided significance level =0.025 for each primary outcome, two sample t test). Accounting for a 20% dropout rate, we planned a total sample size of 215 participants. The predefined analyses have been performed as described in the statistical analyses plan of the trial (version 1.0, available online) and were conducted using SPSS, STATA, and R statistical software.22-24

All randomised participants were included in the full dataset for the intention-to-treat analysis. Group differences for each primary outcome were analysed using two separate analyses of covariance, with baseline measures as covariates and an additional random effect (random intercept model) to account for clustering of participants in centres. The primary outcomes at follow-up (maximal walking speed and Barthel index score three months after stroke) were the dependent variables in these analyses, and baseline scores and intervention group were independent variables. Additionally, we adjusted the analyses for age, sex, and functional impairment (as assessed by the functional ambulation category test). We imputed missing data because of attrition by using multivariate imputation by chained equations (mice) based on 10 imputed datasets and relevant information generated by the R package mice.25 The supplementary appendix provides detailed descriptions of data imputation and handling missing data. If we were unable to assess data on mobility measures at baseline because of severe impairment, reasonable single value imputation was carried out by using half the speed of the slowest participant in the group. Analyses of safety endpoints were done using Poisson regression models, which account for the time each participant is at risk and allows incidence rate and incidence rate ratios with confidence intervals to be calculated.

Prespecified subgroup analyses for the primary outcomes were exploratory for sex, age groups, type of stroke, impairment measured by NIHSS and functional ambulation category, and time from stroke to start of intervention. For each subgroup analysis, we tested the interaction between treatment allocation and subgroup to test whether any difference in treatment effect between subgroups was substantial. For each subgroup we also provided mean treatment effects and 95% confidence intervals.

Secondary outcome measures were analysed using a three level mixed model where the repeated measures were nested in participants and participants were nested in centres. We used baseline variables of outcomes as covariates. Models were additio nally adjusted for age, sex, and baseline functional ambulation category. In all models we included interaction terms for time point and treatment group. Reported effect estimates were calculated using postestimation procedures. All models (except for mRS and functional ambulation category) are based on 10 imputations with chained equations and groupwise imputation (see supplementary table S3). For the mRS and functional ambulation category, we used an ordinal logistic mixed regression model including respective covariates for adjustment and random intercept to account for repeated measures. The group variable for centre was entered as fixed covariate in the ordinal mixed models to avoid instability of models. Variables with non-normal distribution were log transformed before analyses. All secondary analyses were carried out in an exploratory framework. No adjustment for multiple testing was applied for secondary analyses.

doi: 10.1136/bmj.l5101|BMJ 2019;366:l5101 | thebmj

BMJ: first published as 10.1136/bmj.l5101 on 18 September 2019. Downloaded from on 12 January 2024 by guest. Protected by copyright.

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BMJ: first published as 10.1136/bmj.l5101 on 18 September 2019. Downloaded from on 12 January 2024 by guest. Protected by copyright.

Patient and public involvement Before and during the trial, a patient representative appointed by the Berlin Stroke Alliance participated in meetings of the trial's executive steering committee. A member of the trial centre informed the Berlin Stroke Alliance (including participants and family members) about the progress of the trial on a regular basis. After the last trial visit, each participant received a summary of his or her personal outcome measures and blood test results. Findings of the trial will be shared with all

participants by providing access to the full manuscript. The supplementary appendix provides a section for participants and carers who provided additional information.

Results From 26 September 2013 to 30 April 2017, a total of 12866 adults were screened of whom 200 were included in the trial and underwent randomisation (105 were assigned to aerobic physical fitness training

Baseline

12 866 Adults with stroke admitted to rehabilitation sites

12 666 Ineligible 5746 Not seen by recruiter 6699 Not meeting inclusion criteria 51 Declined to participate 4 Screening failure 166 Other reasons

200 Randomised

105 Aerobic physical tness training

95 Relaxation

2 Excluded before training 1 Serious adverse event 1 Early discharge from clinic

Start of intervention

2 Excluded before training 1 Serious adverse event 1 Protocol violations

18 75% participation 1 Protocol violations 5 Serious adverse event 4 Transferred to other clinic 4 Declined to participate 4 Adverse event

Post-intervention

85 Completed 75%

11 75% participation 1 Suspended training >5 days 3 Serious adverse event 4 Transferred to other clinic 1 Declined to participate 1 Adverse event 1 Protocol violations

82 Completed 75%

5

Lost to follow-up

1 Lost contact 2 Refused further visit 1 Serious adverse event 1 Adverse event

11 Lost to follow-up

3 Lost contact 6 Refused further visit 2 Serious adverse event

80 Per protocol set

105 Full analysis dataset

3 months follow-up

71 Per protocol set

95 Full analysis dataset

Fig 1 | Flowchart of enrolment and randomisation. Multiple imputation was performed for intention-to-treat analyses of full analysis dataset

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